1. health and fitness
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Exceptional Medicine
PeaceHealth Southwest Physicians Journal
n
Volume 4, Number1, Fall 2011
“Lung cancer remains the leading
cause of cancer-related death in
North America and is a growing
health crisis across the world.”
—- Riyad Karmy-Jones, MD, FACS, FRCSC
PeaceHealth Southwest Regional Cancer Center
2011 ANNUAL REPORT
FIGHTING A PREVENTABLE DISEASE:
LUNG CANCER DIAGNOSIS, STAGING, AND TREATMENT
Exceptional
Medicine
PeaceHealth Southwest
Physicians Journal
Fall 2011
Volume 4, Number 1
PUBLISHI N G S TA F F
Editorial Director
Kenneth Cole
Contributing Editors
Alden Roberts, MD
Brian Harwood, MD
Submission Guidelines
Exceptional Medicine is a free, editorial-reviewed
publication by credentialed Medical Center staff for
regional physicians.
For complete details and submission guidelines, go
to www.swmedicalcenter.org/exceptionalmedicine
or contact the editorial staff
(kcole@swmedicalcenter.org or 360.514.3066).
TABLE OF CONTENTS
Fighting a Preventable Disease:
Lung Cancer Diagnosis, Staging,
and Treatment
Riyad Karmy-Jones, MD; Dennis Febinger, MD;
William McBride, MD; Fan Zhou, MD; Aruna Reddy, MD;
Kelly Smith, MD; S. Christopher Hoffelt, MD;
Becky Hambright, RN, OCN, CCRP; Clifford S. Pukel, MD;
Marie Tesdale, RHIT, CTR
2
Introduction
3
Epidemiology
4
Solitary Pulmonary Nodule
6
Pathology of Lung Cancer
12 Biomarkers and their Implications in
NSCLS
14 Staging
17 NSCLC vs. SCLC
19 Chemotherapy in the Treatment of Lung
Cancer
20 Evolution of Radiation Therapy
22 Pre-operative Physiologic Assessment
25 Extent of Resection
27 Thoracic Incisions and Approaches
28 Complications of Surgery
29 The PeaceHealth Southwest Experience
31 Lung Cancer and Research
32 Conclusion
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Mission Statement
We carry on the healing mission of Jesus Christ by
promoting personal and community health, relieving
pain and suffering, and treating each person in a
loving and caring way.
© Copyright 2011 PeaceHealth Southwest Medical Center,
Marketing Department, PO Box 1600, Vancouver, WA 98668
Fighting a Preventable Disease:
Lung Cancer Diagnosis, Staging, and Treatment
Lung cancer remains the leading cause of cancer deaths in both men and
women in the United States. In women, deaths from lung cancer became
more common than from breast cancer in 1987, and in men 31% of all deaths
have been attributed to lung cancer. Lung cancer results in more deaths than
colon, breast, pancreas and prostate (the next four most common) combined.
In this report, we examine several facets of lung cancer including diagnosis,
staging, and treatment.
Riyad Karmy-Jones, MD,
Thoracic and Vascular Surgeon
Dennis Febinger, MD,
Thoracic and Vascular Surgeon
William McBride, MD,
Pulmonologist
Fan Zhou, MD,
Pathologist
Aruna Reddy, MD,
Medical Hematologist/Oncologist
Kelly Smith, MD,
Medical Hematologist/Oncologist
S. Christopher Hoffelt, MD,
Radiation Oncologist
Becky Hambright, RN, OCN, CCRP,
Cancer Research Registered Nurse
Clifford S. Pukel, MD,
Medical Hematologist/Oncologist
Marie Tesdale, RHIT, CTR,
Certified Tumor Registrar
Volume 4, Number 1
Correspondence:
Riyad Karmy-Jones, MD
Rkarmyjo@swmedicalcenter.org
PeaceHealth Southwest Medical Center
Regional Cancer Center
PO Box 1600
Vancouver, WA 98668
360-514-2174
www.swmedicalcenter.org/cancercenter
Thoracic and Vascular Surgery
404 NE 87th Avenue, Suite 301
Vancouver, WA 98664
360-514-1854
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1
INTRODUCTION
Lung cancer remains the leading cause of cancerrelated death in North America and is a growing
health crisis across the world. It is particularly
frustrating that this is very nearly a completely
preventable disease, the primary etiology
being self-induced inhalation of carcinogens.
Unfortunately, anywhere from 60-80% of
patients who present with lung cancer are past
the point where real cure can be entertained,
and even in early stage (“curable”) cases there is
a marked risk of recurrence, often in association
with continuing the primary behavior that led
to the cancer in the first place (i.e. smoking)
(Figure 2). 1, 2
Primary lung cancer can be divided into three
basic groups, non-small cell (NSCLC), small
cell, and intermediate or benign (carcinoid).
Small cell cancer is generally NOT a surgical
disease. The primary forms of NSCLC are
adenocarcinoma and squamous cell carcinoma.
These subtypes, as will be discussed, respond
differently to different regimes, and there has
been a great deal of increased understanding of
the genetics of these lesions.
Because there are multiple treatment options
and because patients usually present with
multiple co-morbidities, a multi-disciplinary
approach is required. The primary questions
when a patient presents with a lung mass or
pleural effusion are:
1. What is it?
2.If it is lung cancer, what are the treatment
options?
When discussing treatment of confirmed lung
cancer, it is important to note that treatment can
include surgery, radiation and/or chemotherapy,
or a combination in different sequence. Each
has different variations that can be employed
depending on the circumstances. How to best
choose among the options depends on staging,
which can be considered in two parts.
2
We define the first part for the patient as “how
far has the cancer spread”. This defines the
extent of resection and risk of recurrence after
treatment. The most basic premise is that if the
cancer appears to be limited to one lobe, surgery
plays a critical role in cure. If the cancer has
spread outside of the chest, or to the contralateral lung, surgery has very limited role except
in rare circumstances. If the mediastinal nodes
are involved, and this is known prior to surgery,
then surgery may play a role, but as an adjuvant
therapy following chemotherapy with or without
radiation.
It is also important to recognize “stage
migration”. Thus the 5-year disease-free survival
of clinical stage IA lung cancer is 50%, but of
pathological (i.e. after surgery) is 70-80%. This
is because in a number of cases occult disease
(nodes, pleura, etc.) is found at surgery. In
these cases there is often a role for adjuvant
chemotherapy. On the other hand, some cancers
are found to be smaller or less involved than
anticipated. There is significant variation in
survival based on stage and other factors. The
overall 5-year survival from 1974-1976 was
12.5%, while from 1995-2001 it had increased
to 15.7%. The overall 5-year survival for local
disease was 49%, regional 16%, and distant
disease 2%. 3
The second component of staging is assessing
risk of death or risk to quality of life. In the
simplest terms, what is the risk of respiratory
failure and/or cardiovascular complications?
Certain procedures (such as sleeve resection or
chest wall reconstruction) may be associated
with increased risk of complications.
It is ideal, at the initial consultation, to go over
these issues with each patient. Most patients are
scared, having learned that they may have or do
have lung cancer. Understanding the plan and
steps incorporates them in the decision making
process and allows them to regain autonomy.
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Fall 2011
Figure 1: 10-year Lung Cancer Incidence – PeaceHealth Southwest 2001-2010
The number of lung cancer cases at PeaceHealth Southwest peaked in 2007 at 167.
200
Number of Cases
180
160
146
140
140
149
167
156
147
142
150
2008
2009
135
130
120
100
80
60
40
20
0
2001
2002
2003
2004
2005
2006
2007
2010
Year
Finally, the Achilles heel of therapy is systemic
recurrence. Like other cancers, NSCLC should
be considered a systemic disease. Continued
surveillance is required even after “curative”
treatment. In addition, although most results
are defined in terms of disease-free survival,
a number of patients survive but have
recurrence. The primary point is that while
there is still significant progress to be made, the
multidisciplinary team can treat lung cancer
with the goal, if not of always obtaining a cure, of
extending not only life but also quality of life.
EPIDEMIOLOGY
Lung cancer remains the leading cause of cancer
deaths in both men and women in the United
States. In women, deaths from lung cancer
became more common than from breast cancer
in 1987, and in men 31% of all deaths have been
attributed to lung cancer. Lung cancer results
in more deaths than colon, breast, pancreas
and prostate (the next four most common)
combined. 4
Volume 4, Number 1
The etiology of lung cancer is related to exposure
to toxins and genetic risk factors. Given that
there are multiple risk factors that overlap, one
assessment implicated smoking as the etiology of
cancer in 90% of cases, occupational exposures
9-15%, radon exposure 10%, and outdoor
pollution 1-2%.5
Compared to patients who have never smoked,
smokers have at least a 20-times increased risk of
developing lung cancer. The rate of occurrence
appears to lag by about 20-years from the onset of
smoking. Between 1995 and 1999 in the United
States 122,800 deaths were directly attributed to
smoking-induced lung cancer.6 Cigar and pipe
smokers have an increased risk also, but their
risk is slightly less than that of cigarette smokers,
possibly due to different smoking patterns.
Passive smoking is a risk. Non-smokers married
to smokers have a greater than 30% increased
risk of developing cancer, and nearly one quarter
of the cases of lung cancer in those who have
never smoked has been attributed to passive or
second-hand smoke exposure.
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SOLITARY PULMONARY NODULE
The detection of a solitary pulmonary nodule
(SPN) is a common reason for referral to a
pulmonary or thoracic physician. Improved
understanding of the epidemiology of SPNs and
advances in diagnostic techniques have lead to
evidence-based strategies for their evaluation.
Solitary pulmonary nodules are defined as intraparenchymal lesions less than or equal to 3 cm
in greatest dimension. The majority of SPNs are
incidental findings in asymptomatic patients.7
Currently, many are detected by routine CXR,
although this is likely to change with the
increasing use of CT scanning as a screening
technique.
The prevalence of SPNs in various populations
has been reported in recent studies. A 2007
review of the results of eight screening trials
found SPNs in 8-51% of high-risk patients.8 One
of the largest trials of CT screening for early
detection of lung cancer found SPNs in 13% of
enrollees.9 More recently, the National Lung
Screening Trial reported that 31.6% of such
patients screened with low-dose CT scanning had
positive results which required further evaluation
to exclude lung cancer.10
The ideal clinical evaluation strategy should
accurately distinguish malignant SPNs from
benign lesions while minimizing the morbidity
and cost associated with the evaluation itself.
Several clinical factors have been shown to be
useful in estimating the likelihood of malignancy.
These include the prevalence of malignant SPNs
within the population as well as individual
characteristics such as lesion size, patient age and
whether the patient has been a cigarette smoker.
Several researchers have proposed quantitative
models to estimate the probability of malignancy
in an individual SPN based on these factors.11
4
The majority of SPNs reflect benign disease.
This is especially true for SPNs found on a
CT scan used as a screening tool. In a review
of 955 patients with SPN discovered on plain
CXR from 1983, 51% of lesions were found to
be non-malignant.12 More recently, the NLST
investigators found that 96.4% of SPN detected
on screening CT were non-malignant.10 Benign
SPNs are commonly caused by granuloma (80%)
or hamartoma (10%).
Increased lesion size is associated with increased
risk of malignancy. In one study, the likelihood
of malignancy was 0.2% for nodules smaller
than 3 mm, 0.9% for nodules 4 to 7 mm, 18% for
nodules 8 to 20 mm, and 50% for nodules larger
than 20 mm. 13
The probability of a SPN being malignant is
increased in older patients. One study stratified
the percentage of SPNs that were malignant
according to the patient’s age and found that 3%
of SPNs were malignant in patients between ages
35 and 39, 15% between ages 40 and 49, 43%
between ages 50 and 59, and 50% or higher at
age 60 or above.14
The evaluation of a SPN should be guided by an
evidence-based approach such as one published by
the American College of Chest Physicians.15 The
roles of newer diagnostic techniques including
endobronchial ultrasound bronchoscopy (EBUS)
and electromagnetic navigation bronchoscopy
(ENB) have not been fully defined. They
complement standard bronchoscopy, CT-guided
biopsy and surgical biopsy.
In summary, a SPN is a common reason for
referral to specialists for clinical evaluation. The
evaluation should be evidence-based and utilize
newer, minimally invasive techniques.
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Fall 2011
Table 1: Proposed IASLC ATS ERS Classification for Small Biopsy Samples
2004 WHO Classification
IASLC/ATS/ERS Classification for Small biopsy
Adenocarcinoma
Mixed subtype
Acinar
Papillary
Solid
Adenocarcinoma, with a variety of special patterns
Bronchioloalveolar carcinoma
(nonmucinous)
Adenocarcinoma with lepidic pattern
Bronchioloalveolar carcinoma
(mucinous)
Mucinous adenocarcinoma
Fetal
Adenocarcinoma with fetal pattern
Mucinous (colloid)
Adenocarcinoma with colloid pattern
Signet ring
Adenocarcinoma with signet ring cell features
Clear cell
Adenocarcinoma with clear cell features
Solid adenocarcinomas
Non-small cell carcinoma, favor adenocarcinoma
Squamous cell carcinoma
Papillary
Clear cell
Small cell
Basaloid
Squamous cell carcinoma, with specific features
Squamous cell carcinoma
Non-small cell carcinoma, favor squamous cell carcinoma
Small cell carcinoma
Small cell carcinoma
Large cell carcinoma
Non-small cell carcinoma, NOS
Large cell neuroendocrine
carcinoma (LCNEC)
Non-small cell carcinoma with neuroendocrine (NE) morphology,
possible LCNEC
Large cell carcinoma with NE
morphology (LCNEM)
Non-small cell carcinoma with NE morphology (negative NE markers)
Adenosquamous carcinoma
Non-small cell carcinoma, with squamous cell and adenocarcinoma
patterns. This could represent adenosquamous carcinoma.
Adenosquamous carcinoma
Non-small cell carcinoma, NOS, equivocal immunostains. This could
represent adenosquamous carcinoma.
Sarcomatoid carcinoma
Poorly differentiated NSCLC with spindle and/or giant cell
carcinoma.
Modified from Travis WD, et al. J Thorac Oncol 2011; 6:244.
Volume 4, Number 1
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Table 2: IASLC ATS ERS Classification of Lung Adenocarcinoma in Resection Specimens
Preinvasive lesions
Atypical adenomatous hyperplasia
Adenocarcinoma in situ (≤3 cm, formerly BAC)
Nonmucinous
Mucinous
Mixed mucinous/nonmucinous
Minimally invasive adenocarcinoma (≤3 cm lepidic predominant tumor with ≤5 mm invasion)
Nonmucinous
Mucinous
Mixed mucinous/nonmucinous
Invasive adenocarcinoma
Lepidic predominant (formerly nonmucinous BAC pattern, with >5 mm invasion)
Acinar predominant
Papillary predominant
Micropapillary predominant
Solid predominant with mucin production
Variants of invasive adenocarcinoma
Invasive mucinous adenocarcinoma (formerly mucinous BAC)
Colloid
Fetal (low and high grade)
Enteric
Modified from Travis WD, et al. J Thorac Oncol 2011; 6:244.
PATHOLOGY OF LUNG CANCER
Tissue diagnosis and classification of lung
malignancy has currently undergone a
revolutionary change. Diagnosis of a generic
non-small cell carcinoma is no longer
acceptable, and separation of adenocarcinoma
from squamous cell carcinoma should always
be attempted. Immunohistochemistry and
molecular testing have been increasingly utilized
to further classify adenocarcinomas into several
treatment- appropriate groups. Multiple testings
often exhaust the small amount of tumor tissue
sample. Tissue sample preservation should be
carefully planned ahead since small biopsies are
apparently now the majority sample type for
initial diagnosis of lung cancer. Tumor pathology
is now beyond just morphologic assessment.
6
Combined efforts from clinicians, radiologists
and pathologists are required to achieve a
clinically meaningful diagnosis.
I. Classification
Traditionally, classification of lung carcinoma
has been based mainly on H&E sections
of biopsies or cytologic preparations. The
tumors were grouped essentially into two
types: small cell carcinoma and non-small
cell carcinoma. The 2004 World Health
Organization (WHO) schema of lung tumors
has been the foundation for lung cancer
classification. In 2011, a multidisciplinary
expert panel representing the International
Association for the Study of Lung Cancer
(IASLC), the American Thoracic Society
(ATS), and the European Respiratory Society
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Fall 2011
(ERS) proposed a major revision of the
classification system, primarily reworked
the classification of adenocarcinomas. The
diagnostic terms are sometimes phrased
differently when the diagnostic specimens
are small biopsies (Table 1) compared to the
large excisional specimens (Table 2).
Most of the lung cancers are carcinomas or
epithelial tumors (>98%). Roughly 20% of
the carcinomas are small cell carcinoma,
and 80% of them are non-small cell
carcinoma (NSCLC). Amongst the NSCLC,
30% are squamous cell carcinoma, 60%
adenocarcinoma and 10% other carcinomas
including large cell carcinoma. These
numbers may vary in different regions of
the world such as Europe where squamous
cell carcinoma is still more common than
adenocarcinoma.
Adenocarcinoma
Adenocarcinoma is defined as an epithelial
tumor with glandular differentiation and/
or mucin production. Some tumors may
not have the typical adenocarcinoma
morphology but express markers typical for
adenocarcinoma (TTF-1, CK7, Napsin A and
Mucin). These tumors should be signed out
as NSCLC, favor adenocarcinoma. Possibility
of adenosquamous cell carcinoma cannot
be entirely ruled out. New development
in this 2011 adenocarcinoma classification
includes recognition of morphological
heterogeneity, pathologic sequence of
tumorigenesis (dysplasia, carcinoma in situ
and invasive carcinoma), and molecular
as well as radiologic association with
different adenocarcinomas. The term
bronchioloalveolar carcinoma (BAC) has
been eliminated and is now replaced with
adenocarcinoma in situ, minimal invasive
adenocarcinoma, or lepidic adenocarcinoma.
Volume 4, Number 1
Atypical adenomatous hyperplasia
(AAH)
AAH is a localized, small (<0.5cm)
proliferative disease of alveolar lining cells.
AAH is composed of cuboidal round cells
with frequent nuclear inclusions. It may be
regarded as a high-grade dysplasia in the
sequence of lung cancer carcinogenesis.
AAH is found in 9-16% of patients with lung
cancers, often adenocarcinomas. AAH is
often multifocal, which explains the frequent
incidence of multicentric synchronous and
metachronous carcinomas of the lung.
Adenocarcinoma in situ (AIS)
AIS is a localized, small adenocarcinoma
(<3cm) with a restricted growth along the
framework of alveoli, or so called lepidic
growth pattern. No apparent stromal,
vascular or pleural invasion should be seen.
Papillary and micropapillary patterns are
absent. The vast majority of AIS tumors
are previously known as non-mucinous
bronchioloalveolar carcinoma (BAC), and
they should have minimal nuclear atypia.
Typical mucinous BAC is not included here.
Minimal invasive adenocarcinoma
(MIA)
MIA is a small, solitary adenocarcinoma
(<3cm) with a predominant lepidic pattern
and an invasive tumor less than 5mm in
any focus. Tumors are excluded from this
category if they invade lymph-vasculatures,
pleural membrane, or exhibit tumor necrosis.
Patients with MIA, like AIS, had reported a
100% 5-year survival rate.
Invasive adenocarcinoma (IAC)
IAC consists of over 70% of the surgical
resected lung cancers. The invasive
component should measure more than
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5 mm in greatest dimension. Invasion is
defined by non-lepidic growth pattern, and
myofibroblastic reaction associated with
the invasive tumor. Many of these tumors
show a mixture of complex heterogeneous
histologic subtypes. The previous mixed
subtype is eliminated since over 90% of the
IAC are mixed. An adenocarcinoma should
be classified according to its predominant
pattern and other subtypes should also
be listed with a percentage attached. The
major histologic patterns include acinar,
solid, papillary, micropapillary, lepidic, and
mucinous histologies. Acinar predominant
adenocarcinoma contains mostly malignant
Glands or cribriform histologies, and is still
the most common histology with an average
clinical aggressiveness. Lepidic predominant
adenocarcinoma (LPA) predicts an excellent
prognosis with a 90% 5-year recurrencefree survival. Micropapillary predominant
adenocarcinoma is apparently associated
with worse clinical outcomes. Solid
predominant adenocarcinoma also shows an
unfavorable prognosis. Papillary predominant
carcinoma is normally of intermediate grade
or clinical aggressiveness.
Some histologic subtypes preferably host a
particular molecular mutation. Mucinous
adenocarcinoma, formerly mucinous BAC
is strongly associated with KRAS mutations
(80-100%), rarely EGFR mutation. Signet
ring cell carcinoma and clear cell carcinoma
are commonly classified within the
adenocarcinomas of the solid pattern. More
than 50% the cases with the EML4-ALK
fusion mutations have the signet ring cell
histology. The rest of ALK+ cases are found
in the acinar histology. EGFR mutations
are almost equally represented amongst
the different subtypes of the non-mucinous
adenocarcinomas but are significantly lower
in tumors of the acinar histology and almost
absence from the mucinous adenocarcinoma.
8
Squamous cell carcinoma (SCC)
Squamous cell carcinoma is defined as
epithelial carcinoma showing keratinization
and / or intercellular bridges. Over 90% of
squamous cell carcinomas occur in cigarette
smokers and the majority of them arise
centrally in the mainstem, lobar or segmental
bronchi. Histologic variants include
papillary, clear cell, small cell and basaloid
SCC. Typical squamous cell carcinomas
are positive for CK5/6, p63, and 34BE12 by
immunohistochemistry.
Adenosquamous cell carcinoma
(ASC)
ASC is a carcinoma exhibiting both squamous
cell carcinoma and adenocarcinoma
features or coexisting both squamous cell
carcinoma and adenocarcinoma elements
in at least 10% of each tumors. They
express a wide range of low molecular and
high molecular cytokeratins (CK18, CK7,
CK5/6, 34BE12 and p63). ASC usually
has an unfavorable prognosis compared
to pure adenocarcinomas or squamous
cell carcinomas with current treatment
modalities.
Small cell carcinoma (SCLC)
Small cell carcinoma has a small nucleus
that is often smaller than three resting
lymphocytes. SCLC tumor cells have scant
cytoplasm, fine nuclear chromatin and
frequent apoptoses. They are mitotic active
usually over 1 to 5 per HPF. Some difficult
cases may require immunohistochemistry
to determine if the neuroendocrine
differentiation is present. A panel of
antibodies including CD56, chromogranin
and synaptophysin are normally utilized.
Neuroendocrine differentiation does not
define a small cell carcinoma and other
neuroendocrine tumor entities need to be
ruled out.
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Fall 2011
Neuroendocrine carcinoma (NEC)
Neuroendocrine tumors (NET) contain
tumor cells of the “neuroendocrine”
features: smooth nuclear contour, fine
nuclear chromatin, inconspicuous nucleoli
and scant cytoplasm. They often show
organoid nesting, palisading, rosette-like
structure and sometimes nuclear molding.
Most of the NET can be classified into one
of the four categories: typical carcinoid,
atypical carcinoid, large cell neuroendocrine
carcinoma (LCNEC), and small cell
carcinoma (SCLC). A mitotic count of 11 or
more per 10 high power fields is one of the
major criteria separating LCNEC / SCLC
from the carcinoids. Accurate separation
of LCNEC from SCLC can be difficult if
it is not impossible. Some NSCLC tumors
may not have the typical neuroendocrine
morphology, but definitely show
neuroendocrine differentiation (NED) by
immunohistochemistry. These tumors should
be classified as NSCLC-NED.
Large cell carcinoma (LCC)
LCC is a heterogeneous group of
undifferentiated non-small cell carcinomas
composed of large polygonal cells or
anaplastic large tumor cells, and it cannot
be further classified into one of the known
categories. Large cell neuroendocrine
carcinoma, basaloid carcinoma,
lymphoepithelioma-like carcinoma, clear
cell carcinoma and large cell carcinoma with
rhabdoid phenotype are included there. It is
often classified as NSCLC-NOS in the new
classification scheme.
II. Tissue is the issue:
Obtaining pathology samples
Tissue is the issue. A general oncology
dictum says “no meat, no treat”, emphasizing
the critical importance of tissue diagnosis
before starting a therapy with potential
Volume 4, Number 1
side effects. Approximately 70% of lung
cancers are diagnosed and staged on small
biopsies or cytology rather than large surgical
specimens. About 80% of the tumors in the
small samples are diagnostic and adequate
for tumor classification. However about
20% of tumors cannot be classified and are
signed out as NSCLC-NOS. With molecular
profiling and appropriately selected
immunohistochemistry, the NSCLC-NOS
group can be sized down to 10%.
Tissue examination of the primary tumor is
preferred. There are several modalities to
choose for tumor sampling and the selection
is based on the size and location of the
primary tumor in the lung, metastatic status,
and anticipated treatment plan. CT-guided
percutaneous needle aspiration biopsy
(TNAB) tend to have the highest diagnostic
accuracy. However, the bronchoscopic
biopsy allows sampling the peri-bronchial
and mediastinal lymph nodes during the
same procedure. Among the bronchoscopic
techniques, EBUS-guided sampling appears
to be superior to conventional flexible
bronchoscopic sampling of small lesions
(<3 cm), but indifferent for larger lesions.
CT-guided needle biopsy
Transthoracic needle biopsy (TTNB) is the
most commonly used diagnostic procedure
with the diagnostic accuracy over 80%
for benign tumor and reaching 90% for
malignant tumors. Most of the CT-detected
lung cancers are adenocarcinomas, which
often show ground glass opacity (GGO) on
CT. Greater than 75% of tissue diagnostic
accuracy can be achieved for small GGO
(<2cm) whereas the accuracy is improved
significantly to 90% when the TNAB is
performed on a GGO lesion of 2 cm or
greater. The size of the needle used to obtain
biopsy specimens has shown to affect slightly
the diagnostic rate but the 19-G / 20-G
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needles produce significantly less side effects
than 18-G needles. Compared to 20-G
needles, 18-G needles apparently provide
larger specimens (10-15% more or ~10 mg)
and more DNA quantity for future molecular
testing.
Transbronchial biopsy
For central tumor lesions, endobronchial
biopsy provides the highest sensitivity (74%)
followed by bronchial brushing (59%) and
washing (48%). For peripheral tumors,
the sensitivity of bronchial brushing is the
highest (52%), followed by transbronchial
biopsy (46%), and bronchioalveolar lavage/
washing (43%). Diagnosing a peripheral
nodule <2cm by endobronchoscopy and
biopsy was around 33%, in contrast to
62% when the nodules are greater than
2cm. Aspiration, aspiration / biopsy and
cutting needle biopsy are equally capable of
diagnosing lung cancer. Tissue biopsy has
apparent advantage over aspiration for extra
tissue available for immunohistochemistry
and molecular testing.
Thoracentesis
Pleural effusions are present in up to 30%
of all patients with NSCLC. Thoracentesis
detects up to 65% of malignancy.
Examination of pleural fluid is now
mandatory for all patients with NSCLC.
When a malignant effusion is confirmed, the
patient’s pathologic stage will move up to
M1a. An adequate sample requires at least
50 ml of pleural fluid for cytology. If the first
sample is negative, a second thoracentesis is
recommended. About 30% of the initial false
negative cases will be positive in subsequent
samples.
III.Pathology tissue examination and
molecular testing
Recent developments on NSCLC treatment
have had a significant impact on how the
10
NSCLC should be accurately classified.
Adenocarcinoma histology predicts favorable
outcome to pemetrexed therapy in advanced
cancer patients. Patients with squamous
cell carcinoma should not be treated with
bevacizumab due to potential life-threatening
hemorrhage. Adenocarcinomas with the
EGFR mutation have a significantly better
complete response rate and progressfree survival with EGFR-TKI (erlotinib or
gefitinib) treatment. EML4-ALK fusion genes
identify a small group of young patients who
often are non-smokers and their tumors may
be targeted by ALK inhibitor (crizotinib) on
clinical trials. Adenocarcinomas with KRAS
mutations usually show little response to the
treatment using EGFR-TKI. Further testings
on adenocarcinoma of the lung for EGFR,
KRAS, BRAF mutations and EML4-ALK
fusion gene should be considered and testing
strategy and algorithm should be developed.
General specimen requirements for
molecular tests
EGFR or KRAS analysis studies using PCRbased technologies often requires a minimum
of one 8-10 µm unstained FFPE slide with
a tissue surface area equal or greater than
25mm2, containing 25% viable tumor cells
and ideally over 50% of tumor cells on the
tissue section. One H&E stained slide should
be available for pathology assessment. The
pathologist’s task includes selecting the most
tumor rich tissue core that has minimal
stromal cells, inflammatory cells or necrosis.
If tumor cells are less than 25% but more
than 10%, and the tissue sample is abundant,
tumor enrichment by manual or lasercaptured micro-dissection may be performed
to help achieve a reliable testing result. We
should keep in mind that the suggested
minimal tissue amount is for an average
specimen, sample adequacy also depends on
the quality of DNA (fragmentation),
testing technology, and mutation types.
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Fall 2011
DNA fragmentation comes from many
variables that cannot be assessed before
the testing. Fixative type, tissue block age,
time-to-fixation, time-in-fixative, and tissue
type are only a few of the fixation-related
parameters. It has been shown that the best
results are obtained when formalin fixation
time is between 6-12 hours for a small biopsy
and 8-18 hours for a larger specimen.
Specimens for FISH study need to have a
sufficient number of tumor cells with good
quality chromosomal DNA and excellent
cytomorphology as well. An H&E slide
and a 4-6 µm unstained tissue section on a
positively charged slide with more than 50
tumor cells is needed minimally. Ideally the
tissue section should contain some nontumor cells used for internal controls.
Adenocarcinoma with EGFR
mutation
Activating EGFR mutations in the TK
domain result in deregulation of this pathway
and neoplastic proliferation. Such mutations
are often seen in the lepidic, papillary and
micropapillary adenocarcinoma, rarely in
mucinous carcinomas and occasionally in
acinar adenocarcinoma. The recommended
testing method is direct sequencing of PCRamplified DNA targeted around the common
mutations.
Immunohistochemistry using the nonselective anti-EGFR antibodies provides
controversial testing results, and should
not be used for guiding therapy selection.
EGFR FISH may be performed to assess if
an increased copy number of chromosome
7 with or without EGFR amplification.
Only the mutation status provides the best
predictor of potential response to EGFR-TKI
therapy. EGFR mutation is often associated
EGFR amplification, but not always
associated with the EGFR protein expression.
Antibodies to the most common EGFR
Volume 4, Number 1
mutations have been developed and they are
promising tools for identification of specific
EGFR mutations by IHC.
The EGFR mutated tumors may develop
resistance. The primary resistance mostly
comes from the KRAS mutations (insertion
mutation of exon 20), and the secondary
resistance is often associated with T790M
substitution in exon 20 in 50% of these
resistant patients whereas amplification of MET
gene accounts for approximately 20% of the
cases.
Adenocarcinomas with EML4-ALK
fusion gene
Approximately, 5% of NSCLC harbor an
EML4-ALK fusion gene that is created
by inversion within the chromosome 2p.
The EML4-ALK fusion gene is often found
in signet-ring cell carcinoma, mucinous
carcinoma and solid carcinoma subtypes.
Tumors of predominant lepidic histology are
rarely associated with the ALK fusion gene.
FISH analysis with a break-apart probe for
ALK gene is currently the preferred test. The
tumors with EML4-ALK may be screened by
immunohistochemistry using antibodies to
the fusion protein antigen.
Adenocarcinoma with KRAS mutation
Ras mutations are commonly associated with
adenocarcinoma and rarely squamous cell
carcinoma. KRAS mutations are identified in
up to 30% of pulmonary adenocarcinomas.
Adenocarcinomas with activating KRAS
mutations tend to be smaller tumors with
a poorly differentiated histology and often
show mucinous and micropapillary as the
dominant pattern. Whether KRAS mutation
is a reliable predictor for resistance to TKI
drugs remains controversial. KRAS mutation
test is normally performed on a FFPE tumor
tissue sample by sequencing after PCR
amplification.
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11
Adenocarcinoma with BRAF
mutation (BRAF and MAP kinase
pathway)
About 3% of pulmonary NSCLC have
somatic mutations in BRAF. Near half of the
mutations are V600E. Tumors with BRAF
mutations often exhibit micropapillary,
papillary and lepidic histologic patterns.
Patients with BRAF mutated tumors have
shown better clinical outcome compared
with those with KRAS mutations.
Summary
Selecting therapy based on histologic subtype
and molecular mutation status is now changing
the landscape of how a lung cancer is classified
and tested. Adenocarcinoma must be reliably
differentiated from squamous cell carcinomas
primarily by histomorphology assisted by
immunohistochemistry. When adenocarcinoma
is diagnosed, defining subtype and testing for
molecular mutations are required for most cases.
Preservation of the tumor samples during the
diagnostic workup should be actively managed.
A reflex testing protocol or well-thought testing
algorithm will help use the tissue sample
effectively and minimize the need for re-biopsy.
Selecting molecular testing methodology is
also critical, since not all commercial tests
are created equal, or clinically relevant. EGFR
mutation analysis is currently the test of choice,
not EGFR over expression by IHC or gene copy
amplification by FISH. Adequate assessment
during the needle biopsy procedure and tumor
tissue selection before molecular testing by
a pathologist will help assure an accurate
diagnosis, quality result of molecular testing and
decrease re-biopsy procedure.
BIOMARKERS AND THEIR
IMPLICATIONS IN NSCLC
For decades tumors have been classified based
on histological analysis of stained tissue sections
for diagnosis and classification. Novel research
techniques have provided deeper insight into
12
the molecular basis of cellular transformation
and have demonstrated the heterogeneity
that exists at a molecular level even in tumors
that are in a similar subclass.16 It is common
knowledge that in the metastatic setting in
Non Small Cell Lung Cancer (NSCLC) only
a subset of patients with any specified type of
cancer benefit from chemotherapy. This is not
surprising given the molecular heterogeneity
of tumors. Systematic sequencing of cancer
genome has identified several abnormalities
including chromosomal aberrations and
deletions, overexpression of oncogenes, deletions
or mutations of tumor suppressor or DNA repair
genes.17 In some situations these altered genes
or the proteins they encode are targets for new
drug development and in other cases they serve
to predict prognosis or response to treatment.
A prognostic marker is a biomarker that is
indicative of patient outcome independent of
the treatment received. A predictive marker
is a biomarker that is indicative of therapeutic
efficacy and can be a target for therapy.18 In
NSCLC, the prognostic and predictive value of
several biomarkers has been explored. Examples
include activating mutations involving the
epidermal growth factor receptor (EGFR) and
oncogenes KRAS and the EML4-ALK (anaplatic
lymphoma kinase) genes.
EGFR is involved in cell cycle regulation, and
the intracellular domain of the EGFR includes
a tyrosine kinase (TK), which plays a critical
role in cell signaling and carcinogenesis in
selected patients with NSCLC.19 KRAS oncogene
is expressed in virtually all mammalian cells
and is believed to regulate signal transduction
pathways that control cell growth and activate
mutations resulting in cell growth. ALK (anaplatic
lymphoma kinase) is a receptor tyrosine kinase
and its exact role in human biology is not clear.
Activating mutations in the TK domain of EGFR
or chromosomal rearrangement mutations leading
to the fusion oncogene EML4-ALK (echinoderm
microtubule associated protein like-4 and anaplatic
lymphoma kinase) can result in production of
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Fall 2011
potent kinases that result in deregulation of the cell
cycle promoting tumor growth.20
NSCLC.26 EGFR, KRAS and ALK mutations are
all mutually exclusive.
EGFR mutations are more common in
adenocarcinomas, women, never smokers or
light smokers defined as 10-pack-years or less,
are found in about 10% of NSCLC in the Western
population versus 30% in Asians. Tyrosine kinase
inhibitors (TKIs) that target EGFR including
Gefitinib and Erlotinib are available. EGFR does
not appear to be prognostic independent of
therapy but is predictive of response to tyrosine
kinase inhibitors (TKIs). ALK mutation is found
in 3-4% of all NSCLC, is more common in never
smokers or light smokers; about 90% of ALK
positive patients are never or light smokers. It is
also seen in adenocarcinomas and more so with
signet ring features. An ALK kinase inhibitor,
Crizotinib, that targets the ALK rearrangement
is also available. EGFR and ALK mutations can
be tested by immunohistochemistry (IHC) or
fluorescence in situ hybridization (FISH) or
mutation analysis. ALK can be detected by IHC
using an ALK specific antibody. However, FISH
is more sensitive and specific for detecting
the EML4-ALK gene rearrangement.21 EGFR
mutation status is a better predictor of response
to TKIs in NSCLC than FISH or IHC.22 EGFR
and ALK mutations are mutually exclusive.
Other markers that have been studied include
excision repair cross complementation group
1 (ERCC-1) and ribonucleotide reductase-M1
(RRM-1). These genes have multiple effects;
including repair of damage to DNA. High
ERCC-1 levels are prognostic of better survival
compared to low levels independent of therapy.
High levels are predictive of poor response to
platinum based chemotherapy. High RRM-1
levels are prognostic of better survival compared
to low levels independent of therapy. High levels
are predictive of poor response to Gemcitabinebased therapy.27,28 Multiple other biomarkers
are being studied and preliminary results are
encouraging but they need to be validated and
tested in larger settings.29,30
Response rates for mutation-positive tumors
with specific inhibitors average about 60-70%,
and the responses are typically longer lasting
than with traditional chemotherapy.23,24 A phase
3 randomized trial, PROFILE 1007 comparing
Crizotinib to standard chemotherapy in ALK
positive NSCLC has completed accrual. A phase
1 trial NCT00585195 remains open for ALK
positive NSCLC patients and other solid tumors.
FDA has recently approved Crizotinib for ALK
positive NSCLC.
KRAS mutations occur in up to 30% of NSCLC
patients, predominantly in adenocarcinomas and
have been associated with a poor prognosis.25
KRAS mutation is an independent predictor
of resistance to therapy with EGFR-TKIs in
Volume 4, Number 1
The absolute survival benefit of chemotherapy
in the adjuvant setting is about 4.2% at 5 years.31
This suggests that large numbers of patients
who do not benefit from adjuvant therapy will
receive it. Translational research is focusing on
identifying subsets of patients who would benefit
from adjuvant therapy, and this may in future
help provide individualized therapy. Researchers
at MD Anderson Cancer Center explored a novel
statistical model to match Erlotinib, Erlotinib
with Bexarotene, Sorafenib or Vandetanib to
specific tumor molecular profiles in patients
with advanced NSCLC who had previously
received other therapies as part of a phase II
trial.32 The first 97 patients were randomized
equally to the four treatments and subsequently
adaptive randomization was employed whereby
information from treated patients’ biopsies and
outcomes was employed to guide assignment of
drugs to new patients.
Biopsy specimens were analyzed for various
molecular markers and correlated with responses
and outcomes. It is interesting to note that 61% of
patients with a KRAS mutation in their tumors who
took Sorafenib had disease control at eight weeks,
compared with 32% for the other three drugs.
Erlotinib worked best against EGFR mutations;
Exceptional Medicine
13
Vandetanib for high VEGFR-2 expression and the
Erlotinib-Bexarotene worked best with Cyclin D1
defects or amplified numbers of the EGFR gene.
These findings are interesting and need to be
confirmed and validated in larger settings.
Figure 2: AJCC Lung Cancer Stage at
Diagnosis PHSW 2010
41% of patients diagnosed with lung cancer at
PeaceHealth Southwest in 2010 were Stage IV.
1%
To summarize, the complex pathogenesis of
NSCLC involving multiple pathways is just
beginning to be unraveled. Novel research
techniques may pave the way for possible
personalized medicine in the near future.
Stage 3
Stage 4
22%
Anatomic staging provides a rational basis for
choosing among the many options for treating
non-small cell lung cancer.33 It is critical to
understand that lung cancer should be thought
of as a systemic disease not a mere local process,
and patients need to understand that part of
what we try and achieve by staging is to predict
whether chemotherapy and/or radiation can play
a role in reducing late recurrences.
As noted, in the simplest terms, if the cancer is
limited to the lung, then surgery plays the preeminent role. If the cancer has spread beyond the
chest, except in certain specific circumstances,
surgery has no role to play, and definitive
chemotherapy and/or radiation therapy is employed.
If the central mediastinal nodes are involved then
either pre-operative chemotherapy (sometimes with
radiation) or definitive chemotherapy/radiation
(occasionally followed by surgery) is employed.34
If there is extensive local invasion (chest wall,
vertebra, possibly great vessel) then pre-operative
radiation and/or chemotherapy is often utilized to
provide better systemic
treatment and to “shrink”
the tumor, hopefully
techniques may pave
providing a “sterile”
the way for possible
margin (Tables 4-7).34 In
personalized medicine in general, if surgery can be
incorporated into therapy,
the near future.
survival is improved.
Disease-free survival following surgery for Stage I-II
NSCLC is 50-80% and for intermediate (IIIA) 2540% following induction therapy.
14
Stage 2
26%
STAGING
Novel research
Stage 1
41%
Unknown
11%
Techniques of staging
If there is evidence of extra-thoracic metastatic
disease, every effort should be made to rule
this out. In general, the most common areas
of suspicion are pleural effusion, liver and/
or adrenal metastases. These can be biopsied
or aspirated, but on occasion thoracoscopic or
laparoscopic exploration may be required.
Most of the issues concerning staging relate
to lymph node assessment (Figure 3, Table 3).
Supraclavicular lymph nodes that are suspicious
may be sampled by image-guided biopsy or cut
down. Cervical mediastinal nodes (along the
trachea) are accessible to mediastinoscopy.
Aorto-pulmonary nodes are generally approached by
anterior mediastinotomy. Anterior mediastinotomy
may be performed to assess how fixed a left upper
lobe lesion or nodes are to mediastinal structures or
Table 3: Lymph Node Assessment
Technique
Nodal Stations
Within Reach
Mediastinoscopy
2,3,4, anterior 7
Anterior
Mediastinoscopy
5,6
Endobronchial
Ultrasound
2,3,4,6,7,10.11
Endoesophageal
Ultrasound
Posterior 2 & 4,7,8,9
VATS
5,6,10,11
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Fall 2011
Table 4: TNM Classification
TX
Positive cytology only
T1
< 3 cm
T1a
< 2 cm
T1b
>2-3 cm
T2
Main bronchus > 2 cm from carina, invades visceral pleura, partial atelectasis
T2a
>3-5 cm
T2b
>5cm – 7 cm
T3
>7 cm; chest wall, diaphragm, pericardium, mediastinal pleura, main bronchus < 2 cm
from carina, total atelectasis, separate nodule(s) in same lobe
T4
Mediastinum, heart, great vessels, carina, trachea, esophagous, vertebra; separate tumor
nodule(s) in different ipsilateral lobe
N1
Ipsilateral peribronchial and/or hilar
N2
Subcarinal, ipsilateral mediastinal
N3
Contralateral mediastinal or hilar, scalene or supraclavicular
M1
Distant metastasis
M1a
Separate tumor nodule(s) in Contralateral lobe; pleural nodules or malignant effusion
(pleural or pericardial)
M1b
Distant metastasis
Table 5: Stage Grouping
Occult carcinoma
TX
N0
M0
Stage 0
Tis
N0
M0
Stage IA
T1a,b
N0
M0
Stage IB
T2a
N0
M0
Stage IIA
T2b
T1a,b
T2b
N0
N1
N1
M0
M0
M0
Stage IIB
T2b
T3
N1
N0
M0
M0
Stage IIIA
T1a,bT2a,b
T3
T4
N2
N1,2
N0,1
M0
M0
M0
Stage IIIB
T4
Any T
N2
N3
M0
M0
Stage IV
Any T
Any N
M1
Volume 4, Number 1
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15
Table 6: Staging in NSCLC
Stage
Primary Treatment
Adjuvant Treatment
I
Surgery
None
II
Surgery
Chemotherapy NOT RT
IIIA (N2 found pre-op)
Definitive Chemo/RT
Possibly Surgery
IIIA (N2 found intra-op)
Chemo/RT
IIIB
Definitive Chemo/RT
Rare Surgery
IV
Definitive Chemo/RT
Rare Surgery
Table 7: Survival by Stage after RO Resection
Stage
5 yr survivial (%)
IA=T1N0M0
IB=T2N0M0
IIA=T1N1M0
55%
IIB=T2N1M0
39%
IIB=T3N0M0
Relapse Rate (%)
Local
Distant
67%
10
15
57%
10
30
38%
12
40
IIIA=T3N1M0
25%
Rare Surger
IIIA=T1-3N2M0
23%
15
2R
2L
4R
Figure 3:
Lymph Node
Regions
4L
3
10R
60%
6
10L
7
11R
16
11L
8R
8L
9R
9L
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Fall 2011
Figure 4: PET Scan: Large Tumor, Right
Upper Lobe
The majority of the uptake is central, suggesting
the peripheral portion of the mass may represent
post-obstructive bronchitis rather than tumor
extension.
the main pulmonary artery. Cancers that are solidly
fixed are often not amenable to surgical resection.
Endobronchial (EBUS) and endoesophageal (EUS)
ultrasound-guided approaches have become more
prominent.35,36
It is tempting to use PET scan as the primary
staging modality, but the accuracy and
dependability can vary from patient to patient.
Large central tumors have a higher risk of
mediastinal node involvement. Cancers with
relatively low PET uptake may present with false
negative mediastinal PET studies. Alternatively,
PET scans can be falsely positive in the setting of
extensive lung inflammation or in regions where
granulomatous infections are endemic (Figure 4).
Pleural effusions usually portend extensive
disease. Aggressive attempts at excluding the
presence of malignant cells should be performed,
including in all but small effusions pleural
aspiration and not infrequently thoracoscopic
exploration prior to resection.
NSCLC VS. SCLC
There are several types of lung cancer, and they
are divided into two groups – non-small cell
lung cancer (NSCLC) and small cell lung cancer
(SCLC) – based on their behavior, staging,
Volume 4, Number 1
treatment and prognosis. NSCLC accounts
for approximately 80% of lung cancers and is
defined as any type of epithelial lung cancer
other than SCLC.37 Adenocarcinoma, squamous
cell cancer and large cell cancer are the three
most common types of NSCLC. SCLC comprises
about 15% of lung cancers. Whereas NSCLC,
particularly adenocarcinoma, can occur in nonsmokers, SCLC is almost always associated with
tobacco use.37
NSCLC and SCLC appear differently under the
microscope. SCLC is characterized by sheets of
small cells with scant cytoplasm, finely granular
nuclear chromatin and absent or indistinct
nucleoli with light microscopy. In addition, the
presence of neuroendocrine granules can be
detected with electron microscopy.38 NSCLC has
abundant cytoplasm, coarse nuclear chromatin
and prominent nucleoli with glandular or
squamous architecture.37 Immunohistochemical
staining of SCLC is typically positive for markers
of neuroendocrine differentiation including
chromagranin A, neuron-specific enolase,
neural cell adhesion molecule (NCAM) and
synaptophysin. Ten percent of NSCLC will
be immunoreactive for one or more of these
markers of neuroendocrine differentiation, so
these results cannot be used alone to distinguish
SCLC from NSCLC.39
SCLC often presents as a hilar mass with
bulky mediastinal lymphadenopathy. Among
NSCLC tumor types, adenocarcinoma and
large cell carcinoma tend to be peripherally
located while squamous cell cancer tends to be
centrally located. SCLC is commonly associated
with paraneoplastic syndromes.37 Neurologic
syndromes are immune-mediated and include
Lambert-Eaton myasthenic syndrome, cerebellar
ataxia, sensory neuropathy, limbic encephalitis,
encephalomyelitis, autonomic neuropathy, and
retinopathy.40 Tumors can also secrete hormones
including vasopressin and adrenocorticotropic
hormone (ACTH) causing syndrome of
inappropriate antidiuretic hormone secretion
(SIADH) and Cushing’s syndrome, respectively.37
Exceptional Medicine
17
Table 8: Estimated Cancer Deaths from Lung Cancer - 2010
In 2010, lung cancer deaths in Washington State accounted for nearly 2% of the nationwide total.
Estimated Cancer Deaths from Lung Cancer – 2010
n Washington State – 3,110
n United States – 157,300
*Data from ACS Cancer Facts and Figures 2010 and National Cancer Institute
NSCLC and SCLC have different staging systems.
NSCLC is classified as stage I through IV based
on tumor size, regional lymph node involvement
and presence of distant metastases. Only onethird of NSCLC is diagnosed at an early stage
and is amenable to potentially curative therapy.37
SCLC is classified as either limited or extensive
stage. Limited stage disease is defined as being
encompassed within one radiation port and is
usually limited to one hemithorax. Extensive
stage disease is defined as disease that extends
beyond this area. Most patients present with
distant disease, however, 30-40% of patients
have limited-stage disease at diagnosis.41
NSCLC is much less sensitive to chemotherapy
and radiation than SCLC. SCLC is associated
with a 50-75% response rate to chemotherapy.
Patients often experience quick tumor shrinkage
with rapid improvement in tumor-related
symptoms. Unfortunately, these tumors will
usually relapse and become drug resistant.
NSCLC, on the other hand, is associated with
only a 25-35% response rate to chemotherapy.37
Treatment strategies for NSCLC and SCLC
cancer are different. Surgical resection offers
the best chance for long-term survival and cure
in patients with resectable NSCLC. Surgical
resection is indicated for good surgical candidates
with stage I and II NSCLC.42 Poor surgical
candidates may benefit from radiotherapy.43
Adjuvant chemotherapy in stage IB, II and
III patients has been shown to improve
survival.44 The treatment of Stage IIIA disease is
18
controversial and can include either concurrent
chemoradiation or surgery with neoadjuvant
or adjuvant chemotherapy.37 Stage IIIB disease
is treated with concurrent chemoradiation.45
Platinum-containing doublets are used for
stage IV disease.46 SCLC is usually considered a
systemic disease due to its tendency to be widely
disseminated at the time of diagnosis. Surgical
resection followed by adjuvant chemotherapy
is only attempted in a small number of patients
(about 5%) with stage I (T1-2, N0) disease.47
Chemotherapy given concurrently with radiation
to the thorax is recommended for other patients
with limited-stage disease whereas combination
platinum-based chemotherapy is the cornerstone
of treatment for patients with extensive-stage
disease.41,48,49,50 Patients with a complete or
very good partial remission with induction
chemotherapy should receive prophylactic cranial
radiation in order to decrease the risk of brain
metastases and prolong 3-year survival by 5%.51,52
SCLC has a worse prognosis than NSCLC. SCLC
has a more aggressive clinical course with a rapid
doubling time and propensity to spread quickly.
Without treatment, the median survival of SCLC
is only 2-4 months. With treatment, the median
survival is 14-17 months for limited-stage disease
and 9-10 months for extensive-stage disease.37
The median survival for NSCLC is 59 months for
stage IA, 42 months for stage IB, 34 months for
stage IIA, 23 months for stage IIB, 14 months for
stage IIIA, 8 months for stage IIIB and 4 months
for stage IV disease.53
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Fall 2011
Table 9: Lung Cancer First Course Treatment by AJCC Stage PHSW- 2010
Stage III and IV cancers were most often treated with a combination of diagnostic procedure, radiation,
and chemotherapy.
Stage I
Stage II
D
3
1
4
17
1
26
D,S
6
3
0
1
0
10
D,R
23
8
5
8
0
44
D,C
0
0
2
8
0
10
D,S,C
1
1
3
0
0
5
D,R,C
0
0
15
12
0
27
D,S,R,C
0
0
0
1
0
1
R,C
0
0
0
4
0
4
S
1
0
0
0
0
1
C
0
0
0
1
0
1
Other/No txt
0
2
0
4
0
6
34
15
29
56
1
135
Total
Stage III
Stage IV
Unknown
Total
D = Diagnostic procedure
DS = Diagnostic procedure, surgery
D,R = Diagnostic procedure, radiation
D,C = Diagnostic procedure, chemotherapy
D,S,C = Diagnostic procedure, surgery, chemotherapy
D,R,C = Diagnostic procedure, radiation, chemotherapy
D,S,R,C = Diagnostic procedure, surgery, radiation and chemotherapy
R,C = Radiation, chemotherapy
S = Surgery alone
C = Chemotherapy
CHEMOTHERAPY IN THE
TREATMENT OF LUNG CANCER
The use of various chemotherapy agents in the
treatment of both early stage and advanced lung
cancer is now well established. There are several
drugs and drug combinations which are typically
used in either increasing the likelihood of cure in
patients with early stage disease or extending the
life of patients with more advanced disease. Very
often we use combinations of both chemotherapy
and radiation treatment together in what is
commonly called concurrent chemoradiation.
Carboplatinum, Taxol, gemcitabine, Navelbine,
docetaxel, and pemetrexed are all used in various
treatment schemes and regimens very often in
what are called doublets (i.e. two chemotherapy
Volume 4, Number 1
drugs combined). The use of biological agents
such as bevacizumab, which is a monoclonal
antibody that inhibits blood vessel development,
and through that mechanism may sometimes
help in controlling advanced lung cancer, has
also been shown to have some modest benefit.
Other drugs used in the setting of the treatment
of small cell lung cancer includes etoposide,
carboplatinum, cisplatin, irinotecan, and
topotecan, which in a similar fashion are used
in various combinations in treating both limited
stage and extensive stage disease. Once again,
in small cell lung cancer we very often combine
radiation therapy with these drugs to increase
the likelihood of a meaningful and sustained
response.
Exceptional Medicine
19
More recently, drugs which fall under the general
rubric of chemotherapy, but are more specifically
called targeted therapy, modify various enzyme
pathways. Tyrosine kinase inhibitors such as
erlotinib and gefitinib can be used to treat lung
cancer patients with adenocarcinoma, and
sometimes significant benefit can be achieved
with a very modest degree of toxicity with
these agents. Genetic testing is now performed
to determine who would most likely benefit
from these and other drugs, and gene mutation
analyses of EGFR, KRAS, and ALK which can help
predict the likelihood of a response to these oral
agents.
EVOLUTION OF RADIATION
THERAPY FOR NON-SMALL CELL
LUNG CANCER CONTINUES TO
IMPROVE OUTCOMES
Modifying the immune response to cancer with
cancer vaccines and by other novel approaches
is an area of interest which hopefully over the
next decade will translate into more effective
and less toxic therapies for the treatment of
cancer, specifically in preventing or reducing the
likelihood of disease recurrence.
Lung cancer remains the leading cause of cancer
death in the United States and worldwide.
Most cases are categorized as “non-small
cell carcinomas,” (NSCLC) which is a group
consisting of several subtypes. Squamous cell
carcinoma, adenocarcinoma, and large cell
carcinoma are the most common. Radiation
therapy is a local therapy, and similar to surgery,
the therapeutic use of radiation for NSCLC
depends more on stage and potential for surgical
intervention than type.
One of the fundamental difficulties we have
encountered in the treatment of lung cancer is a
process called tumor heterogeneity where tumor
cells have already mutated, and so in treating a
mass measuring one centimeter or greater, you
are dealing with billions of cells, some of which
are inherently resistant to the chemotherapy
drugs administered. Very often we see an initial
response to treatment based on shrinkage of the
tumor on CT scans, but then recurrent disease
develops in many other locations. This is a
source of great frustration and disappointment to
patients, their families, physicians, and nurses.
Nevertheless, continued efforts to create more
specific and elegant methods of treatment will
help prolong patient’s lives and also, of great
importance, create a much better quality of life
by reducing the side effects of drugs that are very
often only modestly effective.
20
Radiation therapy, or the use of x-rays to destroy
cancer cells, has been an important component
of lung cancer treatment for more than 100 years.
While the early use of radiation therapy was
largely limited to palliation of symptoms, recent
technology and carefully designed clinical trials
have firmly established radiation as a component
of standard care for most stages and types of lung
cancer.
Stage I
Stage I NSCLC includes tumors limited to a
relatively small area of the lung, without evidence
of spread to lymph nodes or distant areas in
the lung or body. For decades, surgery has been
the mainstay of treatment for early stage lung
carcinoma. Surgical techniques continue to
improve, and generally confer cure rates from
60-90% for stage I disease.
For patients unfit for surgery, radiation therapy
was historically a poor second line method
of treatment. Six to eight weeks of treatment
was standard yet cumbersome, damaging to
lung, and resulted in poor cancer control rates,
40-50%.54 Innovations in radiation therapy
delivery, including image guidance, intensity
modulated radiation therapy, and highly accurate
beam delivery have allowed more aggressive
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Fall 2011
treatment with substantially greater dose in fewer
treatments, delivered with minimal collateral
effects. This technique has been called stereotactic
radiation, stereotactic ablative radiotherapy, or
radiosurgery. A large body of evidence, including
data from PeaceHealth Southwest Medical Center,
has routinely demonstrated 90% or greater
control rates and brought this treatment to the
first line of care for medically inoperable stage I
and selected stage II NSCLC patients.55,56
Outcomes for this subgroup of patients treated
at PeaceHealth Southwest were presented at the
annual meetings of the American Society for
Radiation Oncology Annual Meeting in 2010, and
updated for the CyberKnife Robotic Radiosurgery
Summit, 2011.
Sixty-one patients were treated for biopsyproven stage I carcinoma of the lung, receiving
3500cGy to 6000cGy in three to five sessions
with the CyberKnife, an image-guided robotic
radiotherapy system. Control of the treated site of
disease was 94%, survival was 77% at three years,
and toxicity was primarily mild. Example cases
shown in (Figures 5 and 6) represent the typical
success seen with this treatment.
Stage II, III
Stage II and III non-small cell lung carcinomas
primarily consists of disease with evidence of
spread to one or more adjacent lymph nodes.
Lung cancer in this stage is still considered
curable, and as discussed elsewhere in the
annual report, anatomic resection plays an
important role and can be curative. However,
complete gross total resection does not guarantee
cure nor local disease control; local and
regional failure rates from 6 to 65% have been
reported, depending on extent of lymph node
involvement.57 For this reason, postoperative
radiation therapy (PORT) directed toward tumor
bed and/or regional lymph nodes has been
studied and used frequently as an adjuvant to
prevent recurrences. While PORT seems sensible
and beneficial, major benefit has been difficult to
demonstrate in clinical trials. A nonrandomized
Volume 4, Number 1
meta-analysis of the Surveillance Epidemiology
and End Result Database suggested worse
survival with PORT in stage I and II disease
and improved survival in stage III disease when
mediastinal lymph nodes are involved.58 Two
randomized studies have shown improved
recurrence-free survival, but no improvement in
survival. As a result, PORT can be recommended
after surgery for patients with N2 disease.59,60
About 35% of patients with non-small cell lung
cancer have stage III disease, which generally is
considered locally advanced. Surgery, radiation,
and chemotherapy have been used alone or most
often in combination as an attempt at cure.
However, survival is generally poor, and patients
often have comorbidities complicating ideal
treatment delivery. Concurrent chemotherapy
and radiation therapy has emerged as the best
known treatment for stage III NSCLC without
resection. Many prospective studies such as
CALGB 9431 and the LAMP trial have defined
the standard as a two-drug platinum-based
regimen with radiation therapy with 60-63Gy
over 6-7 weeks. This modern treatment course is
extremely difficult with severe toxicity routinely
in 25% or more of the patients, but survival has
improved as a result. Median survival is beyond
16 months in most studies, substantially better
than prior decades. Newer radiation delivery
techniques such as IMRT have allowed safer
dose escalation, which along with new systemic
therapies represent the current focus of lung
cancer clinical trials.
Advanced Lung Cancer
Unfortunately up to 25-50% of lung cancer
patients present with advanced disease,
generally incurable. Radiation plays a very
common and effective role in the palliation
of symptomatic brain, bone, liver, and lung
metastases with little to no impact on survival.
However, as chemotherapy and targeted drugs
demonstrate improvements in survival, the use
and importance of local therapy may expand for
selected patients.
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21
Figure 5: Example Case 1
77-year-old male, stage IA left
upper lobe adenocarcinoma,
recent MI and COPD
precluded surgery, 6000cGy in
3 fractions delivered in 2007.
Three years later there is no
evidence of recurrence.
Figure 6: Example Case 2
73-year-old female, stage
IB poorly differentiated
adenocarcinoma of the right
middle lobe, central by RTOG
criteria. FEV1 = 1.1, dyspnea
symptoms precluded surgery.
5400 cGy in 3 fractions
delivered in 2007. Three and
a half years later there is no
evidence of recurrence.
Conclusion
Every stage of lung cancer has seen measurable
improvements in survival over the past decade.
As outlined in this section, innovations in
radiation therapy and prospective clinical trials
continue to demonstrate the role of radiation
as an effective sole modality for early stage
NSCLC and as a component of therapy for
more advanced stages. Current clinical trials
will continue to define the proper role of each
treatment modality to minimize toxicity and
continue the trend toward better survival.
22
PRE-OPERATIVE PHYSIOLOGIC
ASSESSMENT
While anatomic staging plays a key role in
determining what options may be optimal
from an oncologic sense, staging should also
encompass an assessment of risks of a particular
intervention. These are not exact as one would
like and vary in specificity with regards to
both risk of in-hospital mortality and qualityof-life impact. The key areas that need to be
assessed are lung function, cardiac risk factors,
emotional and nutritional status. While the
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Fall 2011
risk of all complications is assessed, the critical
complications are death, respiratory failure, and
myocardial infarction.61
Approximately one quarter of patients with
non-small cell lung cancer present with clinical
stage I disease. Of these, less than one-fifth have
reduced pulmonary function.62 Untreated stage
I lung cancer has a rapidly declining survival
curve, from 80% at one year, to 50% at 18
months and virtually 100% by three years.63
While many patients are at risk for mortality due
to other causes (cardiac, stroke, respiratory), this
high death rate means that in all but the most
debilitated patients some attempt at treatment
should be considered. Balancing the risk benefit
of surgery and extent of surgery (lobectomy,
segmentectomy or wedge) with a non-surgical
procedure (cyberknife, radiofrequency ablation,
cryoablation) or “medical” treatment is usually
difficult but critically important.
The first chance for assessment is in the initial
consultation. Does the patient have active
bronchitis, asthma and/or other lung diseases?
Is the patient still smoking? A simple test is to
walk the patient for a few minutes or even up
two flights of stairs. Oxygen saturation less than
90% at rest or desaturate greater than 5% with
exertion, have six minute walk less than 500 ft
and/or climb greater than 12 ft are at increased
risk.64 If the patient’s heart rate increases more
than 20% this is a sign of deconditioning.61
Many patients are relatively sedentary and may
have occult cardiac or coronary disease. Signs
and symptoms of cor pulmonale (leg swelling,
orthopnea) should be sought for. Emotional
status can affect choices. Patients who are
depressed or have chronic pain issues may not be
able to tolerate certain approaches or participate
reliably in postoperative care. Malnourished
patients can have problems with wound healing.
Smaller body habitus patients may have more
postoperative neuropathic pain, while obese
patients are at increased risk of deep venous
thromboembolism and wound infection.
Volume 4, Number 1
All patients require pulmonary function tests.
The basic tests include FEV1 and DLCO. These
can be standardized by age, weight and gender.
FEV1 greater than 80% predicted is generally
thought to be sufficient for pneumonectomy,
greater than 60% for lobectomy. Patients with
DLCO and/or FEV1 less than 60% predicted may
require split lung function testing. By quantifying
perfusion to areas of resection the predicted post
operative (PPO) percentage can be calculated for
FEV1, DLCO and Maximal Voluntary Ventilation
(MVV). If PPO percentage for either FEV1 or
DLCO is less than 40%, further steps may be
required, including rehab, aggressive smoking
cessation, and/or further testing, including
MVO2 (Figure 7). Patients in these categories
are at increased risk of death and/or prolonged
respiratory failure. Some patients can improve
enough with smoking cessation that surgery does
become possible.
Many patients who are deconditioned have
cardiac risk factors, including right heart
failure, coronary artery disease and/or rhythm
disturbances. Intra-pericardial resections and
pneumonectomy are associated with an increased
risk of supra-ventricular dysrythmias. Lung
resection is considered “intermediate” risk (<5%
reported cardiac risk generally). Patients who are
active and have no prior history or symptoms to
suggest an increased risk factor generally do not
require further evaluation. Patients with prior
history of vascular disease, coronary symptoms,
deconditioning and/or evidence of heart failure
who are undergoing more than a wedge resection
generally do undergo some screening.
The assessment of psychological status is
harder to define. Some patients have extreme
anxiety and depression, but post-operatively
are so relieved that they do extremely well.
Other patients and/or family have become
so despondent and co-dependent that postoperative care is difficult. Patients who will
not do incentive spirometry for example, or
who have such pain issues that the slightest
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23
Figure 7: Step-wise Assessment of Pulmonary Function in Patients Undergoing Lung
Resection
This assessment assists in determining when to offer or defer surgery as treatment.
Spirometry
FEV1 > 80%
DLCO > 80%
FEV1 < 80%
DLCO < 80%
FEV1 > 40%
DLCO > 40-50%
MVO2
VO2 Max > 15 ml/kg/min
PPO-VO2 Max > 10ml/kg/min
VO2 Max < 15 ml/kg/min
PPO-VO2 Max < 10ml/kg/min
Defer Surgery
24
Offer Surgery
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Fall 2011
incision will be perceived as disabling may not
be good candidates for surgery. Patients who are
malnourished may need supplementation preoperatively and should be cautioned about the
possible need for post-operative tube feeding.65
Age need not be a contraindication to surgery
with curative intent. For patients older than
70 years, mortality for lobectomy appears to be
4-7% and pneumonectomy 14% while for those
younger than 70, mortality following lobectomy
ranges from 1-4% and pneumonectomy 5-9%.64
Some patients older than 80 years may also
undergo surgery with curative intent, with 30-day
mortality ranging between 1.6-8.8%.63, 66
Ultimately, these tests and assessments, while
giving some basis for discussing risks and benefits
of operation, are only guidelines. Each patient
will need to be individually assessed and involved
in making the decision.
EXTENT OF RESECTION
The basic principles of resection are as follows:
1. The tumor and draining lymph complex should
be completely resected when possible;
2.The tumor should be completely excised
without spoilage or traversing;
3.Any structure involved should be resected en
bloc to achieve clear margins;
4.Multi-station lymph node sampling should be
performed and if hilar nodes are involved as
complete a resection as possible be performed.
There has been ongoing debate about whether
lobectomy is required for all T1N0 NSCLC
lesions. The Lung Cancer Study Group published
a series in 1995 that demonstrated as threefold
increase in loco-regional recurrence after wedge
and 2.4-fold increase with segmental resection
compared to lobectomy. This translated in the
follow up to a nearly significant difference in
cancer-free survival. 67
More recently, given improved imaging and
pre-operative staging, it has been argued that
Volume 4, Number 1
peripheral lesions 2 cm or smaller can be
adequately managed with segmental or wedge
resection, although in general the margin should
be about the same size as the primary.68 Mery
and colleagues noted that the survival advantage
of lobectomy was not apparent for patients older
than 71 years.69 It was not entirely clear how many
of these older patients had significant morbidities
and reduced life expectancy. These arguments
can be summarized as follows: Lobectomy is still
the standard of care in patients with adequate
cardiopulmonary status; for patients who are
medically frail, wedge may be appropriate; proper
and complete lymph node staging is critical.
Lobectomy
Pneumonectomy is
is still
generally associated
with a reduced survival
the standard of care in
compared to lobectomy.
patients with adequate
This may be due to
cardiopulmonary status
more locally advanced
cancer requiring larger resection, but it also
has been linked to long-term morbidity related
to loss of lung function and cardiac stress.
Both Deslauriers et al and Ludwig et al noted
improved 5-year survival for sleeve lobectomy
compared to pneumonectomy when matched for
stage (T and N status). Deslauriers’ group noted a
lower loco-regional recurrence (22%) with sleeve
lobectomy vs. pneumonectomy (35%) (Figure 8
and 9).70 Mortality rates are generally the same
or lower than standard lobectomy and airway
complications less than 3%.71
Pulmonary artery involvement may mandate
pneumonectomy. However, tumors or fixed
nodes at the apical branches of both upper
lobe pulmonary arteries, or upper lobe cancers
involving the pulmonary artery in the fissure,
may be managed by lateral resection (usually
closed primarily) or true sleeve resection with
end-to-end reconstruction. Survival is primarily
influenced by stage ranging from 5-year disease
free for N0 disease of 60% to 25% for N2
disease.72
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25
Figure 8: CT Scan Showing Tumor
Involving Origin of the Right Upper Lobe
Bronchus
Figure 9: Principles of Right Upper Lobe
Sleeve Lobectomy
Standard amputation of the bronchus could be
expected to leave a positive margin.
Correlating extent of surgery with stage
Pathological stage I disease after complete
resection has 60-70% 5-year disease-free
survival. Stage 1A tumors do not benefit
from adjuvant therapy. Some Stage IB may,
depending on specific prognostic factors (microvascular invasion etc), benefit from adjuvant
chemotherapy, although this is still debated.
Completely resected pathologic Stage II disease
has a 5-year disease-free survival of 40-50%, with
two thirds of relapses being systemic. There is
emerging consensus that adjuvant chemotherapy
increases disease-free survival.
Thus,
Locally advanced
cancer requires en
bloc resection. As
noted previously,
the majority of
these patients
have undergone
preoperative
chemotherapy and/or
radiation therapy. There is evidence that induction
therapy with chemotherapy improves 5-year
survival following resection, and there appears
in most
patients, pneumonectomy
(especially right sided)
after chemotherapy, with or
without radiation, should
be avoided in most cases.
26
to be an increased advantage with the addition
of pre-operative radiation therapy, particularly
for T3 (chest wall) lesions.73 Typical cases of
T3 resection include chest wall, pericardium
and/or diaphragm (Figures 10 and 11). More
advanced T4 cases may involve partial resection
of superior vena cava, partial left atrial resection,
great vessel resection or vertebral resection.73,
74 Locally advanced tumors can be managed by
induction chemotherapy and/or radiation therapy
with excellent results. For example, with apical
(Pancoast) cancers, after induction therapy,
completely resected posterior tumors with
negative nodes have up to 40-50% 5-year diseasefree survival; while anterior (including vessel
resection) have up to 30% 5-year disease-free
survival.73, 75 Yildizeli and colleagues reviewed 271
patients with locally advanced (T4) non-small cell
cancer who underwent resection. 30-day mortality
was 4% and major morbidity 35%. Overall 5-year
survival was as follows: mediastinal (including left
atrium, esophagus or aorta)-61.2%; carina-42.5%;
superior sulcus-36.6%; superior vena cava29.4%.74 These data demonstrate that resection
for locally advanced cancer is still possible, albeit
at an increased risk.
Surgery after induction therapy is generally
felt to be associated with increased risk of
complications. In one review, complications
after all forms of resection occurred in 38%
of patients, of which 16% were major.76 In
particular, pneumonectomy is associated with
increased mortality and complications related
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Fall 2011
Figure 10: Posterior Apical Tumor Post
Induction Chemoradiation
to stump dehiscence. Thus, in most patients,
pneumonectomy (especially right sided) after
chemotherapy, with or without radiation, should
be avoided in most cases.
The most common problem facing clinicians
is the question of whether or not resection can
be performed in the presence of N2 disease.
When N2 (Stage IIIA) disease is confirmed preoperatively, surgery becomes adjuvant therapy,
following chemotherapy (with or without
radiation therapy). If there is a good clinical
response the patient may be a candidate for
resection with curative intent, albeit with the
caveats discussed earlier. Port and associates
found that a 50% or greater reduction in SUV by
PET was associated with a significantly greater
disease-free survival, and this can be used to
help determine whether or not the patient can
undergo surgery with curative attempt.77 Patients
who do undergo resection, and who require
lobectomy, can have as high as a 25% 5-year
disease-free survival.78 The problem is that this
will not be known until surgery, and it is not clear
that patients with residual disease do any better
than those who did not undergo surgery. Survival
after resection of “occult” N2 disease is still in
the 25-30% range (i.e. in patients who did not
have documented N2 disease prior to resection).
Adjuvant chemotherapy will be required.
In summary, for patients who are a good
operative risk and when appropriate staging does
Volume 4, Number 1
not indicate mediastinal N2 disease (clinical stage
I), lobectomy is the standard of care except for
small peripheral lesions, older patients, or those
with reduced pulmonary reserve. Patients with
clinical stage II disease (confirmed by biopsy)
may benefit from induction chemotherapy,
but generally surgery is performed and if
confirmed there is data that supports adjuvant
chemotherapy. Patients with stage IIIA disease
proved prior to resection generally undergo
induction chemo-radiation therapy, and then are
either restaged and if a good response may be
offered adjuvant surgical resection. Lobectomy or
sleeve lobectomy is preferred to pneumonectomy
if R0 resection is possible.
THORACIC INCISIONS
AND APPROACHES
The principles of lung resection require that
there be complete resection of gross tumor,
that there be extensive lymph node resection
for accurate staging and possibly better cure
rates, and that it be done safely. The standard
approach has been postero-lateral thoracotomy.
This usually involves dividing the latissimus dorsi
while attempts are made to spare the serratus
anterior. Partial or occasionally complete muscle
sparing is associated with quicker functional
recovery of the shoulder. Usually one or two
ribs are “shingled” (cut) to reduce postoperative
pain but patients commonly experience a numb
patch anteriorly and should be warned of this.
Anterior thoracotomy or sternotomy may also be
used in specific settings. In general we reserve
sternotomy for anterior cancers involving the
subclavian vessels or superior vena cava, or for
mediastinal invasive cancers like thymic cancer.
Thoracoscopy refers to procedures performed
using a camera. Some minimal procedures
(wedge resection, pleurodesis) are possible with
only two or three small sub-centimeter incisions.
In rare circumstances, this medical thoracoscopy
can be performed under local anesthesia. VideoAssisted Thoracic Surgery (VATS) refers to
any procedure performed under thoracoscopic
Exceptional Medicine
27
Figure 11: Operative View
After an en-bloc resection of the upper lobe and
three levels of posterior ribs with reconstruction
with bio-prosthetic material, all margins were clear
and nodes negative.
guidance, including formal anatomy lung
resection. VATS lobectomy requires an additional
access port, in the anterior axillary line, which
can vary in length but the critical difference is
that rib spreading is not performed (Figure 12).
VATS lobectomy for early stage lung cancer now
is accepted to have the same oncologic result as
formal lobectomy, as long as the basic principles
of resection are observed. VATS lobectomy
appears to be associated with a quicker recovery
time and less morbidity than “open” thoracotomy,
although up to 7% of patients still experience
intercostals pain, and the risks of air leak and
other complications are similar to thoracotomy.
COMPLICATIONS OF SURGERY
The most common complication that patients
want to discuss is, not unnaturally, the risk of
death. In general mortality following lobectomy
is quoted as 1-4% and pneumonectomy 6-9%. The
majority of deaths does not occur intra-operatively,
but arise from post-operative complications.
Pneumonectomy after radiation is associated with
a marked increase in risk and most centers believe
that it is contra-indicated, although some report
good results with 5-year disease-free survival in the
35% range in well-selected patients.
The primary risk factors relate to pulmonary issues,
particularly pneumonia and respiratory failure.
28
The leading factors contributing to these are
post-operative pain and active lung inflammation
secondary to recent or ongoing smoking. Pain can be
minimized by using thoracoscopic approaches, nerve
blocks, pain catheters and/or epidurals. Recently,
there is evidence that pre-medication with Lyrica,
Tylenol and Celebrex is associated with reduced
pain post operatively. Muscle sparing incisions are
also associated with quicker recovery and less pain.
Patients who are smoking should stop for at least
two weeks and any signs of active bronchitis should
be sought out and treated by appropriate antibiotics.
Cardiac dysrhythmias occur anywhere from
2-30% of patients. Risk factors include
pneumonectomy and intra-pericardial
resections. There is no evidence that supports
prophylactic treatment.
A number of technical complications should
be discussed with patients. Persistent air leak
greater than seven days can be frustrating.
Usually these are managed by putting the chest
drains to Heimlich valve. Nearly 85% will seal
spontaneously over 1-3 weeks.
Bronchopleural fistulas from pneumonectomy
stump leaks occur more often after radiation
therapy, but can be related to empyema, long
stump and/or residual cancer at the resection
line. If noted within seven days, re-operation
is possible via the thoracotomy, but after that
period generally a trans-sternal approach is
recommended. If the fistula is small, claggett
window can be employed, or a combination
approach using omental or muscle flaps with a
clagget type approach.
The most frustrating chronic problem is residual
pain, often accompanied by strips of numbness.
This arises from intercostal nerve injury and can
persist for more than six weeks in about 7% of
patients. Usually this resolves but occasionally
more interventions, such as rib blocks, are
required. This is more commonly a problem with
posterior incisions and small patients due to the
smaller rib spacing, as well as patients with a
history of anxiety, chronic pain and/or depression.
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Fall 2011
Figure 12: Postoperative view after
VATS Lobectomy
Arrow indicates a 5 cm-long accessory site.
THE PEACEHEALTH SOUTHWEST
EXPERIENCE
Starting in late 2006 the oncology community
began a multidisciplinary approach
incorporating the medical oncologists, radiation
oncologists, radiologists, pathologists, pulmonary
physicians and thoracic surgeons. A cornerstone
of this has been a multidisciplinary review
board that meets biweekly to review cases. This
meeting is attended by all three main medical
groups: Southwest Medical Group, Vancouver
Clinic and Northwest Oncology.
From 2006-2010 Southwest Medical Group
performed lung resection on 59 patients with
non-small cell lung cancer (adenocarcinoma 31,
squamous cell 19, undifferentiated or sarcomatoid
8, focal BAC 1) (Figure 13). These numbers do
not include resection of metastases, mediastinal
or thymic cancer resection, esophageal resection,
typical carcinoid, management of malignant
pleural effusion, or any surgery for traumatic or
benign disease. Clinical and pathologic stages are
listed in Figure 14.
Age ranged from 42-84 years (average 66 + 10
years). Thirty-four (58%) were women. Thirtysix (61%) had COPD, defined as FEV1 < 60%
Volume 4, Number 1
predicted, and/or DLCO < 60% predicted, and/
or active bronchitis requiring treatment. Twenty
(34%) had a history of coronary artery disease
defined as prior MI, coronary stent or CABG. All
patients underwent preliminary staging with CTPET, and any with large lesions (> 3 cm), central
lesions, adenopathy > 1 cm, questionable PET +
adenopathy, clinical suspicion for T3 lesions and/
or were deemed high operative risk underwent
mediastinoscopy or EBUS/EUS. Only those with no
evidence of N3 or central N2 disease underwent
resection. Patients who were N2 positive initially
but who after induction therapy and restaging were
N2 negative were considered for resection.
Six (10.2%) underwent induction chemotherapy
and 5 (8.5%) underwent definitive chemoradiation
prior to surgery. Operative and 30-day mortality
was 0. In 19 cases (32.2%) final pathologic stage
was less than initial clinical stage, in 13 (22%)
it was greater (Figure 14). Of patients receiving
induction chemoradiation, no viable cancer was
seen in 6 (54%) of resected specimens.
At an average follow up of 33.9 and 19.6 months,
survival was 88.1% and disease-free survival
72.9%. Two patients died from other disease
without evidence of recurrence, 5 died with
evidence of recurrent disease.
Postsurgical therapy was administered in 24
cases (41%), included chemotherapy in 23.7%,
radiation in 1.7%, chemoradiation in 13.6%, and
cyberknife in 1.7%. The most common reason
was the presence of occult N1 or N2 disease or
vascular invasion. In 18 cases there had not been
any induction therapy.
The overall incidence of recurrence was 14/59
(24%), 2 loco-regionally, the remainder new
lung or metastatic disease. The incidence of
recurrence based on pathology was: BAC 0/1;
squamous cell 3/19 (15.7%), adenocarcinoma
8/31(25.8%); undifferentiated/sarcomatoid
3/8 (37.5%). The impact of stage migration on
5-year survival is reflected by the differences in
clinical and pathological stage outcomes. For
local disease there are better 5-year outcomes for
Exceptional Medicine
29
Figure 13: Procedures Performed for Non-small Cell Lung Cancer at PHSW
VATS lobe procedures made up the majority of procedures performed for non-small cell lung cancer.
30
25
N
20
15
10
5
be
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lo
e
ev
es
ch
y+
pn
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on
ec
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om
ct
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y
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be
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be
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ec
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0
pathological stage IA and IB, while the opposite
is true for loco-regional disease (IIA-IIIA) (Figure
15). This is because some patients with clinically
more advanced disease are found to have more
local (lower stage) disease and vice-versa. Of the
six patients with no viable cancer found, two
(33%) have experienced metastases. Of note,
these patients were all clinical Stage IIIA or IIIB
with mediastinoscopic or EBUS confirmed N2
disease. At an average follow up of 29 and 12
months, four are alive and disease free, one is alive
with recurrence and one patient has died with
recurrence.
This is a review of a small number of patients
with limited 5-year follow up. However, our
experience reflects the national one. At 3-years,
survival for IA was 100%, IB 92%, stage II 78%
and stage IIIA 45% which parallels other reports.
Surgery can be performed safely, in selected
30
patients, even after induction therapy. Induction
therapy does appear to help in “down staging”
patients. Metastases remain the Achilles heel of
cancer therapy, particularly with adenocarcinoma
and undifferentiated cancer. Continued efforts in
early detection, improved staging, and systemic
therapy for what really is a systemic disease are
ongoing. While the overall picture appears grim,
there is hope. Each patient should be addressed
as an individual in a multidisciplinary manner.
Automatic therapeutic nihilism, in which it
is assumed that a patient is not an operative
candidate, should be avoided. At the same time,
careful selection should include not only risks
of mortality, but also risks to quality of life.
Ultimately, a realistic presentation of all possible
options should be presented, but the patient must
make the final decision.
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Fall 2011
Figure 14: Clinical and Final Pathological Stages at PHSW
20
18
Clinical Stage
16
Pathologic Stage
14
12
10
8
6
4
2
0
IA
IB
IIA
IIB
IIIA
LUNG CANCER AND RESEARCH
PeaceHealth Southwest has participated in
organized cancer research since the 1980s. The
four main cancer sites have been our primary
focus: Breast, Colon, Lung, and Prostate. Of
the four, lung cancer remains one of the most
difficult to detect and treat.
Through the years, we have participated in
industry (pharmaceutical-sponsored) clinical
trials, as well as National Cancer Institutesponsored studies made available through the
Community-based Clinical Oncology Programs
(CCOP) and our affiliation with the Columbia
River Oncology Program (CROP). Some of these
studies have included Alimta (Pemetrexed)
for Mesothelioma and Tarceva (Erlotinib) for
metastatic non-small cell lung cancer. Both of
these drugs went on to receive FDA approval
Volume 4, Number 1
IIIB
IV
NO
VIABLE CANCER
based upon the results of many studies, including
the ones that were available here. We have a
variety of clinical trials open at this time for
treatment of various stages of lung cancer, both
small cell and non-small cell.
Currently, we are also participating in a clinical
trial testing a vaccine for a type of non-small cell
lung cancer tumor that expresses the MAGE-A3
gene. Through other research studies, it has
been shown that MAGE-A3 gene expression is
indicative of a tumor that is more aggressive and
more likely to recur when compared to tumors
that do not express the gene. The vaccine has
been developed to try to train the body’s immune
system to respond to these tumor cells wherever
they may be found with the ultimate hope that
we will be able to prevent recurrence for those
patients with MAGE-A3 positive tumors.
Exceptional Medicine
31
Vaccine treatment has been hypothesized
for many years—teaching the body to use its
own immune system to recognize and destroy
tumor cells by training the immune system to
respond to specific genes or proteins found in
the tumor cells. Many hours of laboratory and
clinical research have already been invested in
this type of treatment. Today, it is very exciting
to be a part of this new wave of research and
cancer treatment. As our ability to identify gene
expression and isolate specific proteins found in
tumors improves, immunology becomes the next
major area of cancer management and treatment.
PeaceHealth Southwest remains committed to
participation in clinical research to provide our
patients with state-of-the-art cancer care for all
tumor sites.
CONCLUSION
32
Five-year disease-free and overall survival for local
and loco-regional NSCLC based on clinical and
final pathological stage.
100
Clinical 1A-1B
90
Pathological 1A-1B
Clinical 2A-3A
80
Pathological 2A-3A
70
60
50
40
30
When patients are informed that they have a lung
mass, they are generally appropriately scared. It
is important to let them into the planning phase
early, to explain the role of the various staging
and clinical assessments. Patients often have a
burning desire to proceed quickly to definitive
therapy, but it is not uncommon to have many
confounding variables, such as underlying lung
disease, prior inflammatory lesions, etc. In
general, we aim to have definitive therapy started
within six weeks, but the rapidity of the approach
needs to be balanced by the risk factors to the
patient, including quality of life. Sitting down
with the patient, going over the films, discussing
possible options,
taking them through
the staging process
smoking cessation offers
and just talking with
the best chance to
the patient and their
decrease the incidence of
families may be the
lung cancer and improve
most important aspect
of management.
the chances of survival.
Ultimately
Figure 15: Five-year Survival at PHSW
20
10
0
5-YEAR SURVIVAL
5-YEAR
DISEASE-FREE
SURVIVAL
It is important to note that effective, durable and
tolerable treatments, both for cure and long-term
control of non-resectable cancers, are continuing
to emerge. Physicians should not automatically
take a nihilistic approach to lung cancer. Because
of the multiple issues and options outlined, a
multi-disciplinary approach provides the optimal
treatment. Ultimately smoking cessation offers
the best chance to decrease the incidence of lung
cancer and improve the chances of survival.
www.swmedicalcenter.org
Fall 2011
Figure 16: 10-year Cancer Incidence – PeaceHealth Southwest 2001-2010
The number of cancer cases noted at PeaceHealth Southwest peaked at 1265 in 2009 and dropped to 1092 in 2010.
1300
1265
1255
1250
1232
Number of Cases
1214
1200
1183
1229
1214
1191
1173
1150
1100
1092
1050
1000
2001
2002
2003
2004
2006
2005
2007
2008
2009
2010
Year
Table 10: Comparative Cancer Incidence - 2010
In 2010, lung cancer was the number two cancer incidence at PeaceHealth Southwest. At 12% of all
incidences, PeaceHealth Southwest lung cancer incidences were lower than those of Washington state
(13%) and the US (15%).
PHSW
Site
WA State
Number
Percent
Number
National
Percent
Number
Percent
Breast
304
28
4,900
14
209,060
14
Lung & Bronchus
135
12
4,320
13
222,520
15
Colorectal
88
8
*
*
142,570
9
Corpus/Uterus
57
5
1,010
3
43,470
3
Melanoma
55
5
1,930
6
68,130
4
Lymphoma
54
5
1,600
5
74,030
5
Bladder
53
5
1,720
5
70,530
5
Brain/Other CNS
50
5
*
*
22,020
1
Thyroid
39
4
*
*
44,670
3
Prostate
34
3
5,220
15
217,730
14
223
20
*
*
414,830
27
1,092
100
34,500
100
1,529,560
100
Other
Total
*Washington State and National Data from ACS Cancer Facts and Figures 2010
Volume 4, Number 1
Exceptional Medicine
33
Table 11: PeaceHealth Southwest Primary Site Table - 2010
With 135 cases, lung cancer
was the second most frequently
identified primary cancer site at
PeaceHealth Southwest in 2010.
Primary Site:
Oral Cavity and Pharynx
13
%
1.2
Tongue
5
0.5
Salivary Glands
2
0.2
0.3
Gum & Other Mouth
3
Tonsil
2
0.2
Hypopharynx
1
0.1
152
13.9
7
0.6
10
0.9
5
0.5
Colon
66
6.0
Rectum and Rectosigmoid
22
2.0
Digestive System
Esophagus
Stomach
Small Intestine
Anus and Anal Canal
4
0.4
Liver & Intrahepatic Bile Duct
4
0.4
Gallbladder
2
0.2
Other Biliary
5
0.5
18
1.6
Pancreas
Peritoneum, Omentum & Mesentery
9
0.8
139
12.7
Nose, Nasal Cavity & Middle Ear
1
0.1
Larynx
3
0.3
135
12.4
Bones and Joints
2
0.2
Soft Tissue (including Heart)
4
0.4
Skin excluding Basal & Squamous
59
5.4
Malignant Melanoma – Skin
55
5.0
4
0.4
Respiratory System
Bronchus and Lung (Non-small cell=113, Small cell=22)
Other Non-epithelial Skin
3
0.3
Breast
304
27.8
Female Breast
301
27.5
Basal/Squamous Cell Skin
Male Breast
3
0.3
103
9.4
Cervix
13
1.2
Corpus Uteri
57
5.2
Ovary
14
1.3
Vulva
17
1.6
2
0.2
Male Genital System
44
4.0
Prostate
34
3.1
Female Genital System
Other Female Genital Organs
Testis
9
0.8
Penis
1
0.1
Urinary System
80
7.3
Urinary Bladder
53
4.9
Kidney & Renal Pelvis
27
2.5
Brain & Other Nervous System
50
4.6
Brain
20
1.8
Other Nervous System
30
2.7
Endocrine System
44
4.0
Thyroid gland
39
3.6
Other Endocrine (including Thymus)
Lymphomas
Hodgkin’s lymphoma (Nodal=6)
5
0.5
54
4.9
6
0.5
Non-Hodgkin’s lymphoma (Nodal=35, Extranodal=13)
48
4.4
Myeloma
12
1.1
Leukemia
15
1.4
Lymphocytic Leukemia
3
0.3
12
1.1
Mesothelioma
1
0.1
Kaposi Sarcoma
1
0.1
12
1.1
Myeloid & Monocytic Leukemia
Ill-Defined/Unspecified
34
Number of cases
www.swmedicalcenter.org
Fall 2011
Figure 17: PeaceHealth Southwest Frequency of Cancer by Gender – 2010 Top Ten Sites
Lung cancer was sited in women (69) only slightly more often than in men (66) in 2010.
50
0
100
301
48
40
Colorectal
Site
350
66
69
Lung/Bronchus
0
57
Melanoma
27
28
Lymphoma
29
25
Bladder
13
40
19
31
Brain/Other Nervous System
12
Throid
Prostate
300
3
Breast
Uterus
250
200
150
27
34
0
Number of Cases
Figure 18: PeaceHealth Southwest Major Cancers – Stage at Diagnosis – 2010
In 2010, lung cancer was diagnosed most often at Stage IV.
160
Number of Cases
140
Stage 0
135
Stage 1
120
Stage 2
100
80
60
Stage 3
82
Stage 4
55
56
40
20
Unknown
43
34
29
23
15
9
0
0
Breast
22 18 24
0
6
1
Lung/Bronchus
32
12
5
Colorectal
2
0
6
1
Uterus
6
2
11 8
1 1
Melanoma
Site
Volume 4, Number 1
Exceptional Medicine
35
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Volume 4, Number 1
Exceptional Medicine
37
Enhancing Patient Care Electronically—
Our New SmartChange Newsletter
PeaceHealth Southwest has
a new resource to inform
physicians about the status
of our electronic health
record and related workflow
changes. Our SmartChange
newsletter and SmartPath
website are great resources
for staying informed
on project milestones,
timelines and training dates.
We anticipate some big
changes with our CPOE
implementation next summer
and the conversion to ICD-10
coding by October 2013.
You can view the latest issue of SmartChange by logging onto our SmartPath
website at www.swmedicalcenter.org/smartpath.
PO Box 1600
Vancouver, WA 98668